1-Acyl-7-nitroindoline derivatives, their preparation and their use as photocleavable precursors

Abstract

Photoreleasable compounds comprising a caging moiety linked to an effector moiety represented by structural formula (I) wherein R1 is hydrogen; C1-10 alkyl or substituted alkyl; O(CH2)n-Y; N(COZ)(CH2)mY; or N[(CH2)mY'[(CH2)NY]; R2 and R3 are independently selected from: hydrogen; C1-10 alkyl or substituted alkyl; or R2 and R3 together are cycloalkyl; R4 is hydrogen; C1-10 alkyl or substituted alkyl; phenyl or substituted phenyl; (CH2)nY; or (CH2)mO(CH2)nY; wherein m and n are independently between 1 and 10; Y and Y' are independently selected from hydrogen, CO2H or salts thereof or OPO3<2->, Z is hydrogen or C1-10 alkyl or substituted alkyl; and, X is an effector moiety or a group capable of being coupled or converted to an effector moiety, which are capable of releasing the effector moiety on irradiation, typically by flash irradiation with UV light. The photoreleasable compounds can therefor be used to deliver biologically active effector moieties such as neuroactive amino acids or metal chelators to sites where their activity is required.

What is claimed is:  
     
       1. A compound represented by the structural formula:                    
       wherein 
       R 1  is hydrogen;  
       C 1-10  alkyl or substituted alkyl;  
       ;O(CH 2 ) n —Y  
       N(COZ)(CH 2 ) m Y; or  
       N[(CH 2 ) m Q][(CH 2 ) n y];  
       R 2  and R 3  are independently selected from:  
       hydrogen;  
       C 1-10  alkyl or substituted alkyl; or  
       R 2  and R 3  together are cycloalkyl;  
       R 4  is hydrogen;  
       C 1-10  alkyl or substituted alkyl;  
       phenyl or substituted phenyl;  
       (CH 2 ) n Y; or  
       (CH 2 ) m O(CH 2 ) n Y;  
       wherein: 
       m and n are independently between 1 and 10;  
       Q and Y are independently selected from hydrogen, CO 2 H or salts thereof or OPO 3   2− ;  
       Z is hydrogen or C 1-10  alkyl or substituted alkyl; and,  
       X represents an amino acid.  
     
     
       2. A compound represented by the structural formula:                    
       wherein 
       R 2  and R 3  are independently selected from hydrogen, C 1-10  alkyl or substituted alkyl, or R 2  and R 3  together are cycloaklyl;  
       R 4 ′ is a blocking group; and,  
       X represents an amino acid.  
     
     
       3. The compound of  claim 2 , wherein R 4 ′ is selected from: 
       hydrogen;  
       C 1-10  alkyl or substituted alkyl;  
       phenyl or substituted phenyl;  
       (CH 2 ) n CO 2 Y; and,  
       (CH 2 ) n —O—(CH 2 ) m Y;  
       wherein: 
       m and n are independently between 0 and 10; and,  
       Y is hydrogen, or C 1-10  alkyl or substituted alkyl.  
     
     
       4. The compound of  claim 1 , or a salt thereof, wherein the compound is: 
       Methyl 1-[S-(4-amino-4-carboxybutanoyl)]-7-nitroindoline-5-acetate 10;  
       Methyl 1-(4-aminobutanoyl)-7-nitroindoline-5-acetate 21;  
       1-[S-(4-Amino-4-carboxybutanoyl)]-4-methoxy-7-nitroindoline;  
       1-(4-Aminobutanoyl)-4-methoxy-7-nitroindoline;  
       1-[S-(4-Amino-4-carboxybutanoyl)]-4-methoxy-5-methyl-7-nitroindoline; or  
       1-(4-Aminobutanoyl)-4-methoxy-5-methyl-7-nitroindoline.  
     
     
       5. The compound of  claim 2 , or a salt thereof, wherein the compound is: 
       Methyl 1-[S-(4-amino-4-carboxybutanoyl)]-7-nitroindoline-5-acetate 10;  
       Methyl 1-(4-aminobutanoyl)-7-nitroindoline-5-acetate 21;  
       1-[S-(4-Amino-4-carboxybutanoyl)]-4-methoxy-7-nitroindoline;  
       1-(4-Aminobutanoyl)-4-methoxy-7-nitroindoline;  
       1-[S-(4-Amino-4-carboxybutanoyl)]-4-methoxy-5-methyl-7-nitroindoline; or  
       1-(4-Aminobutanoyl)-4-methoxy-5-methyl-7-nitroindoline.  
     
     
       6. The compound of  claim 1 , wherein X represents a neuroactive amino acid selected from the group of L-glutamate, GABA or glycine. 
     
     
       7. The compound of  claim 2 , wherein X represents a neuroactive amino acid selected from the group of L-glutamate, GABA or glycine. 
     
     
       8. A composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient or carrier. 
     
     
       9. A composition comprising a compound of  claim 2  and a pharmaceutically acceptable excipient or carrier. 
     
     
       10. A composition comprising a compound of  claim 3  and a pharmaceutically acceptable excipient or carrier. 
     
     
       11. A composition comprising a compound of  claim 4  and a pharmaceutically acceptable excipient or carrier. 
     
     
       12. A composition comprising a compound of  claim 5  and a pharmaceutically acceptable excipient or carrier. 
     
     
       13. The compound of  claim 1 , wherein said amino acid is a neuroactive amino acid. 
     
     
       14. The compound of  claim 2 , wherein said amino acid is a neuroactive amino acid. 
     
     
       15. The compound of  claim 3 , wherein said amino acid is a neuroactive amino acid. 
     
     
       16. A composition comprising a compound of  claim 13  and a pharmaceutically acceptable excipient or carrier. 
     
     
       17. A composition comprising a compound of  claim 14  and a pharmaceutically acceptable excipient or carrier. 
     
     
       18. A composition comprising a compound of  claim 15  and a pharmaceutically acceptable excipient or carrier.